# The mechanism of inner ear pressure homeostasis by the endolymphatic sac

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2021 · $397,378

## Abstract

Abstract
Hearing and balance loss is prevalent in every population and poses significant challenges to those affected.
For many types of hearing and balance loss including Meniere's Disease, Enlarged Vestibular Aqueduct
Syndrome, and Pendred Syndrome, the mechanism underlying the disease is currently unknown but is
suggested to result from the loss of endolypmh volume and pressure control in the inner ear. Our long-term
goal is to understand how the exquisite morphology of the inner ear is created during development and
maintained in adults. Here we focus on the role of inner ear fluid pressure regulation by the endolymphatic sac
in this process. The endolymphatic sac is a deeply conserved yet mysterious and poorly studied part of the
inner ear. It has previously been suggested that the endolymphatic sac absorbs excess endolymph but through
an unknown mechanism. Our preliminary data using state of the art timelapse imaging on larval zebrafish
reveals that the endolymphatic sac pulses: the lumenal volume slowly increases over 1-3 hours and then
rapidly decreases over several minutes. Endolymph pressure is necessary and sufficient for the expansion of
the endolymphatic sac, and breaches in the epithelial barrier are necessary and sufficient for its collapse.
These breaches occur at a novel cell-cell junction we term “basal lamellar junctions” that seem to act as
pressure relief valves. These preliminary data support our central hypothesis that regulated breaches in the
epithelial barrier of the endolymphatic sac at specialized pressure relief valves are essential for proper fluid
homeostasis in the inner ear; failure of these pressure relief valves causes endolypmh pressure to build up
leading to inner ear swelling, death of sensory cells, and unregulated tearing of the otic epithelium called
endolymphatic hydrops. We plan to test our central hypothesis using three specific aims: 1) identify the
molecular and cellular mechanisms of valve formation; 2) determine the role of the valve in homeostasis of
endolymph pressure and composition; and 3) determine the structure and function of the valve across species
and developmental stages. Our experimental approach will use functional studies on zebrafish and quail and
descriptive studies on mouse and human. Our studies will employ state of the art 3D, timelapse, confocal
microscopy and serial section electron microscopy along with genetic, pharmacological, and physical
perturbations. At the completion of this project, we will have a deeper understanding of the normal physiology
of the endolymphatic sac and how disruptions to this physiology may lead to disease. Better knowledge of
pressure homeostasis as well as the small molecule reagents we develop will provide a foundation for
development of potential therapeutic interventions for these diseases. We are optimistic that this work will
establish a new causal mechanism for inner ear pressure diseases such as Meniere's.

## Key facts

- **NIH application ID:** 10090586
- **Project number:** 5R01DC015478-05
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** SEAN GREGORY TSUNG-MEGASON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $397,378
- **Award type:** 5
- **Project period:** 2017-02-09 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10090586

## Citation

> US National Institutes of Health, RePORTER application 10090586, The mechanism of inner ear pressure homeostasis by the endolymphatic sac (5R01DC015478-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10090586. Licensed CC0.

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